P
US8222376B2ExpiredUtilityPatentIndex 87

KIR-binding agents and methods of use thereof

Assignee: PADKAER SOEREN BERGPriority: Jan 6, 2005Filed: Jan 6, 2006Granted: Jul 17, 2012
Est. expiryJan 6, 2025(expired)· nominal 20-yr term from priority
Inventors:PADKAER SOEREN BERGWAGTMANN PETER REUMERTSPEE PIETERZAHN STEFANKJAERGAARD KRISTIAN
A61P 31/18A61P 31/14A61P 35/02A61P 31/12A61P 37/00A61P 43/00A61P 35/00A61P 31/00C07K 16/2803C07K 2317/73C07K 2299/00C07K 2317/55C07K 16/28C07K 2317/76
87
PatentIndex Score
14
Cited by
67
References
30
Claims

Abstract

The present invention relates to agents and methods that are capable of augmenting NK-mediated killing of target cells by reducing inhibitory KIR signalling without reducing the binding of KIR to HLA-C. As described herein, transduction of negative signaling via KIR, 5 upon binding of KIR to its HLA class I ligand, can involve a ligand-binding induced, conformational reorientation of the KIR molecules allowing interactions to form between adjacent KIRs in specific domains, leading to accelerated clustering. Methods and agents such as mono-clonal antibodies for reducing KIR-mediated inhibition of NK cell cytotoxicity without reducing or blocking HLA-binding by, e.g., reducing or blocking dimerization of KIR, are provided.

Claims

exact text as granted — not AI-modified
1. An isolated monoclonal antibody or antigen binding fragment thereof that binds to an extracellular portion of an inhibitory human Killer IgG-like Receptor 2DL polypeptide KIR2DL1, KIR2DL2 and/or KIR2DL3, wherein the isolated monoclonal antibody or antigen binding fragment thereof:
 (i) reduces KIR2DL1, KIR2DL2 and/or KIR2DL3-mediated inhibition of NK cell cytotoxicity, and 
 (ii) does not detectably reduce binding between said KIR2DL1, KIR2DL2 and/or KIR2DL3 and an HLA class I ligand of said KIR2DL1, KIR2DL2 and/or KIR2DL3. 
 
     
     
       2. The isolated antibody or antigen binding fragment thereof of  claim 1 , wherein the isolated antibody or antigen binding fragment thereof is a Fab fragment, a Fab′ fragment, a Fab′-SH fragment, a F(ab′)2 fragment, or a multispecific antibody. 
     
     
       3. The isolated antibody or antigen binding fragment thereof of  claim 1 , wherein the isolated antibody or antigen binding fragment thereof is a cross-reactive anti-KIR antibody or an antigen binding fragment thereof. 
     
     
       4. The isolated antibody or antigen binding fragment thereof of  claim 3 , wherein the isolated antibody or antigen binding fragment thereof binds to each of KIR2DL1 and KIR2DL3. 
     
     
       5. The isolated antibody or antigen binding fragment thereof of  claim 4 , wherein the isolated antibody or antigen binding fragment thereof competes with an antibody comprising a VH polypeptide having the amino acid sequence set forth in SEQ ID NO:17 and a VL polypeptide having the amino acid sequence set forth in SEQ ID NO:18 for binding to at least one of KIR2DL1 and KIR2DL3. 
     
     
       6. The isolated antibody or antigen binding fragment thereof of  claim 5 , wherein the isolated antibody or antigen binding fragment thereof comprises the same six complementarity determining regions (CDR's) as an antibody that comprises the VH and VL polypeptides in SEQ ID NO:17 and SEQ ID NO:18. 
     
     
       7. A pharmaceutical composition comprising the isolated antibody or antigen binding fragment thereof according to  claim 1  in an amount effective to detectably potentiate NK cell cytotoxicity in a patient, and one or more pharmaceutically acceptable carriers or diluents. 
     
     
       8. The pharmaceutical formulation of  claim 7 , further comprising a therapeutic agent selected from an immunomodulatory agent, a hormonal agent, a chemotherapeutic agent, an anti-angiogenic agent, an apoptotic agent, and an antibody that blocks HLA-binding to an inhibitory KIR receptor. 
     
     
       9. The pharmaceutical composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof is a cross-reactive anti-KIR2DL antibody or a fragment thereof. 
     
     
       10. The pharmaceutical composition of  claim 9 , wherein the isolated antibody or antigen binding fragment thereof binds to each of KIR2DL1 and KIR2DL3. 
     
     
       11. The pharmaceutical composition of  claim 9 , wherein the isolated antibody or antigen binding fragment is an antibody or antibody fragment that competes with an antibody comprising variable regions having the amino acid sequences set forth in SEQ ID NO:17 and SEQ ID NO:18 for binding to at least one of KIR2DL1 and KIR2DL3. 
     
     
       12. The pharmaceutical composition of  claim 9 , wherein the isolated antibody or antigen binding fragment is an antibody or antibody fragment comprising variable regions having the amino acid sequences set forth in SEQ ID NO:17 and SEQ ID NO:18. 
     
     
       13. An isolated human, chimeric or humanized antibody or antigen binding fragment thereof according to  claim 1 , wherein said isolated antibody or antigen binding fragment thereof is an isolated antibody or antigen binding fragment that competes with an antibody comprising variable regions having the amino acid sequences set forth in SEQ ID NO:17 and SEQ ID NO:18 for binding to at least one of KIR2DL1 and KIR2DL3. 
     
     
       14. The isolated chimeric or humanized or antigen binding fragment thereof according to  claim 13 , wherein said isolated chimeric or humanized or antigen binding fragment is an antibody or antigen binding fragment comprising the CDR H1 region corresponding to residues 31-35 of SEQ ID NO:17, the CDR H2 corresponding to residues 50-66 of SEQ ID NO:17, the CDR H3 corresponding to residues 99-108 of SEQ ID NO:17; the CDR L1 corresponding to residues 24-34 of SEQ ID NO:18; the CDR L2 corresponding to residues 50-56 of SEQ ID NO:18, and the CDR L3 corresponding to residues 89-97 of SEQ ID NO:18. 
     
     
       15. An isolated human, chimeric or humanized antibody or antigen binding fragment thereof that binds to an extracellular portion of an inhibitory human Killer IgG-like Receptor 2DL polypeptide KIR2DL1, KIR2DL2 and/or KIR2DL3, wherein the isolated human, chimeric or humanized antibody or antigen binding fragment thereof:
 (i) reduces KIR2DL1, KIR2DL2 and/or KIR2DL3-mediated inhibition of NK cell cytotoxicity, and 
 (ii) does not detectably reduce binding been replaced with between said KIR2DL1, KIR2DL2 and/or KIR2DL3 and an HLA class I ligand of said KIR2DL1, KIR2DL2 and/or KIR2DL3. 
 
     
     
       16. The isolated human, chimeric or humanized antibody or antigen binding fragment thereof of  claim 15 , wherein the isolated human, chimeric or humanized antibody or antigen binding fragment thereof is a Fab fragment, a Fab′ fragment, a Fab′-SH fragment, a F(ab′)2 fragment, or a multispecific antibody. 
     
     
       17. The isolated human, chimeric or humanized antibody or antigen binding fragment thereof of  claim 15 , wherein the isolated human, chimeric or humanized antibody or antigen binding fragment thereof is a cross-reactive anti-KM antibody or an antigen binding fragment thereof. 
     
     
       18. The isolated human, chimeric or humanized antibody or antigen binding fragment of  claim 17 , wherein the isolated human, chimeric or humanized antibody or antigen binding fragment thereof binds to each of KIR2DL1 and KIR2DL3. 
     
     
       19. The isolated human, chimeric or humanized antibody or antigen binding fragment thereof of  claim 18 , wherein the isolated human, chimeric or humanized antibody or antigen binding fragment thereof competes with an antibody comprising the a VH polypeptide having the amino acid sequence set forth in SEQ ID NO:17 and a VL polypeptide having the amino acid sequence set forth in SEQ ID NO:18 for binding to at least one of KIR2DL1 and KIR2DL3. 
     
     
       20. The isolated chimeric or humanized antibody or antigen binding fragment thereof of  claim 19 , wherein the isolated chimeric or humanized, chimeric or humanized antibody or antigen binding fragment thereof, comprises a VH polypeptide having the amino acid sequence set forth in SEQ ID NO:17 and a VL polypeptide having the amino acid sequence set forth in SEQ ID NO:18 . 
     
     
       21. The isolated chimeric or humanized antibody or antigen binding fragment thereof of  claim 19 , wherein the isolated chimeric or humanized antibody or antigen binding fragment thereof comprises the same six complementarity determining regions (CDR's) as an antibody that comprises the VH and VL polypeptides in SEQ ID NO:17 and SEQ ID NO:18. 
     
     
       22. A pharmaceutical composition comprising the isolated human, chimeric or humanized antibody or antigen binding fragment thereof according to  claim 15  in an amount effective to detectably potentiate NK cell cytotoxicity in a patient, and one or more pharmaceutically acceptable carriers or diluents. 
     
     
       23. The pharmaceutical formulation of  claim 22 , further comprising a therapeutic agent selected from an immunomodulatory agent, a hormonal agent, a chemotherapeutic agent, an anti-angiogenic agent, an apoptotic agent, and an antibody that blocks HLA-binding to an inhibitory KIR receptor. 
     
     
       24. The pharmaceutical composition of  claim 22 , wherein the isolated human, chimeric or humanized antibody or antigen binding fragment thereof is a cross-reactive anti-KIR2DL antibody or a fragment thereof. 
     
     
       25. The pharmaceutical composition of  claim 24 , wherein the isolated human, chimeric or humanized antibody or antigen binding fragment thereof binds to each of KIR2DL1 and KIR2DL3. 
     
     
       26. The pharmaceutical composition of  claim 24 , wherein the isolated human, chimeric or humanized antibody or antigen binding fragment is an antibody or antibody fragment competing with an antibody comprising variable regions having the amino acid sequences set forth in SEQ ID NO:17 and SEQ ID NO:18 for binding to at least one of KIR2DL1 and KIR2DL3. 
     
     
       27. The pharmaceutical composition of  claim 24 , wherein the isolated chimeric or humanized antibody or antigen binding fragment is an antibody or antibody fragment comprising variable regions having the amino acid sequences set forth in SEQ ID NO:17 and SEQ ID NO:18. 
     
     
       28. An isolated antibody or antigen binding fragment thereof according to  claim 15 , wherein said isolated human, chimeric or humanized antibody or antigen binding fragment thereof is an isolated antibody or antigen binding fragment competes with an antibody comprising variable regions having the amino acid sequences set forth in SEQ ID NO:17 and SEQ ID NO:18 for binding to at least one of KIR2DL1 and KIR2DL3. 
     
     
       29. The isolated, chimeric or humanized antibody or antigen binding fragment thereof according to  claim 28 , wherein said isolated chimeric or humanized antibody or antigen binding fragment is an antibody or antigen binding fragment comprising the CDR H1 region corresponding to residues 31-35 of SEQ ID NO:17, the CDR H2 corresponding to residues 50-66 of SEQ ID NO:17, the CDR H3 corresponding to residues 99-108 of SEQ ID NO:17; the CDR L1 corresponding to residues 24-34 of SEQ ID NO:18; the CDR L2 corresponding to residues 50-56 of SEQ ID NO:18, and the CDR L3 corresponding to residues 89-97 of SEQ ID NO:18. 
     
     
       30. The isolated chimeric or humanized antibody or antigen binding fragment thereof according to  claim 29 , wherein said isolated chimeric or humanized antibody or antigen binding fragment is an antibody or antigen binding fragment comprising variable regions having the amino acid sequences set forth in SEQ ID NO:17 and SEQ ID NO:18.

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